Methods and compositions for treating inflammatory bowel diseases relating to human tumor necrosis factor-gamma-beta

Abstract

The present invention encompasses methods for detection, diagnosis, prevention, treatment, and/or amelioration of inflammatory bowel diseases and disorders using TNF-gamma-β and its receptors DR3 and TR6. In particular the invention encompasses methods of using TNF-gamma-β, DR3 and TR6 polypeptides, as well as antibodies, and antagonists thereto, in the diagnosis, prognosis and treatment of ulcerative colitis and/or Crohn's disease. Methods of screening for antagonists of the TNF-gamma-β polypeptide, together with therapeutic uses of such antagonists are also disclosed.

What is claimed is:  
     
         1 . A method for treating or ameliorating a disease or disorder of the gastrointestinal tract comprising administering a composition comprising an antagonist of TNF-gamma-β to a person with, or suspected of having, said disease or disorder.  
     
     
         2 . The method of  claim 1 , wherein said antagonist is an antibody or fragment thereof that specifically binds to a TNF-gamma-β polypeptide consisting of amino acid residues 62-251 of SEQ ID NO:2.  
     
     
         3 . The method of  claim 2 , wherein said antagonist is an antibody or fragment thereof that specifically binds to a complex selected from the group consisting of: 
 (a) a homotrimer comprising a TNF-gamma-β polypeptide consisting of amino acid residues 62-251 of SEQ ID NO:2;    (b) a heterotrimer comprising a TNF-gamma-β polypeptide consisting of amino acid residues 62-251 of SEQ ID NO:2; and    (c) both (a) and (b).    
     
     
         4 . The method of  claim 1 , wherein said antagonist prevents increased secretion of IFN-γ by lamina propria mononuclear cells.  
     
     
         5 . The method of  claim 1 , wherein said antagonist is an antibody or fragment thereof that specifically binds to a polypeptide consisting of amino acid residues 25-201 of SEQ ID NO:4.  
     
     
         6 . The method of  claim 5 , wherein said antagonist is an antibody or fragment thereof that specifically binds to a complex selected from the group consisting of: 
 (a) a homotrimer comprising a polypeptide consisting of amino acid residues 25-201 of SEQ ID NO:4;    (b) a heterotrimer comprising a polypeptide consisting of amino acid residues 25-201 of SEQ ID NO:4; and    (c) both (a) and (b).    
     
     
         7 . The method of  claim 1 , wherein said antagonist is a polypeptide comprising amino acid residues 25-201 of SEQ ID NO:4, or a TNF-gamma-β-binding fragment thereof.  
     
     
         8 . The method of  claim 7 , wherein said antagonist is fused to a heterologous polypeptide.  
     
     
         9 . The method of  claim 8 , wherein said heterologous polypeptide is human serum albumin.  
     
     
         10 . The method of  claim 8 , wherein said heterologous polypeptide is an immunoglobulin Fc domain.  
     
     
         11 . The method of  claim 1 , wherein said antagonist is a polypeptide comprising amino acid residues 31-300 of SEQ ID NO:6, or a TNF-gamma-β-binding fragment thereof.  
     
     
         12 . The method of  claim 11 , wherein said antagonist is fused to a heterologous polypeptide.  
     
     
         13 . The method of  claim 12 , wherein said heterologous polypeptide is human serum albumin.  
     
     
         14 . The method of  claim 12 , wherein said heterologous polypeptide is an immunoglobulin Fc domain.  
     
     
         15 . The method of  claim 1 , wherein said disease is inflammatory bowel disease.  
     
     
         16 . The method of  claim 15 , wherein said inflammatory bowel disease is Crohn's disease.  
     
     
         17 . The method of  claim 15 , wherein said inflammatory bowel disease is ulcerative colitis.  
     
     
         18 . A method of diagnosing a disease or disorder of the gastrointestinal tract comprising detecting abnormal levels of a polypeptide selected from the group consisting of: 
 (a) a TNF-gamma-β polypeptide consisting of amino acid residues 62-251 of SEQ ID NO:2;    (b) a polypeptide consisting of amino acid residues 25-201 of SEQ ID NO:4 or a fragment thereof; and    (c) a polypeptide comprising amino acid residues 31-300 of SEQ ID NO:6 or a fragment thereof, in a biological sample.    
     
     
         19 . The method of  claim 18 , wherein the polypeptide being detected is (a).  
     
     
         20 . The method of  claim 19 , wherein the level of expression of said protein is abnormally elevated.  
     
     
         21 . The method of  claim 18 , wherein the polypeptide being detected is (b).  
     
     
         22 . The method of  claim 21 , wherein the level of expression of said protein is abnormally elevated.  
     
     
         23 . The method of  claim 18 , wherein the polypeptide being detected is (c).  
     
     
         24 . The method of  claim 23 , wherein the level of expression of said protein is abnormally elevated.  
     
     
         25 . The method of  claim 18 , wherein the disease or disorder is inflammatory bowel disease.  
     
     
         26 . The method of  claim 25 , wherein said inflammatory bowel disease is Crohn's disease.  
     
     
         27 . The method of  claim 25 , wherein said inflammatory bowel disease is ulcerative colitis.